Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridines are reportedly useful as inhibitors of 11-β-hydroxysteroid hydrogenase type 1 (“11-β-HSD1”) and for treatment of disorders associated with 11β-HSD1 activity including, for example, diabetes mellitus (e.g., type II diabetes), obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica (see, e.g., WO 2011/057054).
The aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridines can be prepared, for example, from nitrile-substituted hexahydroindenopyridines as described in WO 2011/057054. In one method described in WO 2011/057054, the intermediate (4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (A) is allowed to react with 1H-benzoimidazole-5-carboxylic acid (B) followed by reaction with hydrogen chloride to provide the 11-β-HSD1 inhibitor (4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (C) as depicted below:

Methods of preparing the compound of formula (A) described in WO 2011/057054 include a 13-step synthesis and a low overall yield (˜2.9%). In addition, some of the described methods utilize corrosive and/or toxic reagents (e.g., trifluoromethanesulfonic acid anhydride (Tf2O), boron tribromide (BBr3) and Zinc cyanide (Zn(CN)2), which produce a problematic by-product stream. Thus, there is a need, for improved processes for making compounds of formula (A). Such improvements in making intermediate (A) will allow for more efficient preparation of aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridines inhibitors, particularly for large-scale production.